Who is the "young" factor in human stem cells? April 19, 2019 In our bodies, cell division, aging and death are played every moment, and mesenchymal stem cells, which are widely found in human fat, bone marrow, joints, etc., play a special role. Studies have shown that aging and depletion of mesenchymal stem cells is one of the important causes of osteoarthritis. In order to explore the factors that make the mesenchymal stem cells "rejuvenate", the Liu Guanghui team of the Institute of Biophysics of the Chinese Academy of Sciences conducted a four-year exploration. Their research results were published in the journal Cell Report. Years of urging people Why are many old people who are not able to walk? As we age, the chondrocytes in the joints will slowly age, and the cartilage mucus that is lubricating will also decrease, causing joint pain, stiffness, and even osteoarthritis. The current treatment methods for osteoarthritis mainly include non-drugs, drugs, and surgery. Non-pharmacological means include active exercise, acupuncture, massage, electrotherapy, etc., with few side effects, but limited effect; drug treatment means injection of analgesic, cartilage protective agent, sodium hyaluronate, etc., can quickly eliminate inflammation and promote cartilage healing and regeneration. However, the injection itself will damage the cartilage and should not be used repeatedly; if necessary, surgical treatment will be used, but the operation has certain risks and the effect is difficult to guarantee. Studies have shown that an important cause of osteoarthritis is the aging and functional deterioration of mesenchymal stem (precursor) cells, chondrocytes, and synoviocytes in the joints. Among them, the mesenchymal stem cells can differentiate into chondrocytes, synovial cells, ligament cells, etc. when the joint is aged or damaged. If the key targets leading to the senescence of mesenchymal stem cells can be found and inhibited, the "young state" stem cells can be more effectively differentiated into chondrocytes and synovial cells, thus achieving timely "replenishment and replacement" of aging joint cells. This may be a safer and more effective method than existing treatments. Based on this conjecture, Liu Guanghui's research team has been working hard to explore factors that can restore the "young state" of human mesenchymal stem cells. Young factor shows its ability To find the mystery of rejuvenating mesenchymal stem cells, we must first explore the difference between young and old mesenchymal stem cells. The researchers examined and compared gene expression levels in young and old mesenchymal stem cells, and soon found that in older cell lines, one of the components of the PRC1 protein complex, CBX4, was expressed at a lower level. Significantly lower than younger cell lines. Later, they detected the primary mesenchymal stem cells isolated from the elderly tissue and found the same phenomenon. "CBX4 protein shows a decrease in expression in physiological aging, hereditary accelerated aging, and replicative senescence in mesenchymal stem cells. Given its characteristics as an epigenetic regulator, we suspect that this may be a charge A driving force for aging of stem cells," said Xiao Qing, the first author of the paper and a postdoctoral fellow at the Institute of Biophysics of the Chinese Academy of Sciences. Using the CRISPR/Cas9 technology to target knockout of CBX4, the researchers found that mesenchymal stem cells lacking CBX4 did accelerate aging. Can the overexpression of CBX4 in cells make younger cells younger? To test this, the researchers cloned the CBX4 gene coding sequence into a lentiviral expression vector. This lentiviral vector has been genetically engineered and no longer has the "virulence" of the virus, but can be used as a gene introduction tool to introduce the target protein into mammalian cells, which is a common means in the practice of human disease gene therapy. When lentiviral vectors loaded with the CBX4 gene coding sequence were introduced into senescent human mesenchymal stem cells, these stem cells became more "young" and restored the characteristics of rapid growth. The researchers pointed out that this may be because CBX4 prevents the excessive synthesis of intracellular proteins, thereby slowing the rate of cellular aging. Helping to solve aging-related diseases In addition to cell-level experiments, the researchers conducted animal experiments. They cut the anterior cruciate ligament of the mouse to simulate the occurrence of osteoarthritis. The lentiviral vector overexpressing CBX4 was subsequently injected into the joint space of the mouse. It was found that the proportion of senescent cells in the joint was reduced, the cartilage regeneration was obvious, the inflammatory reaction was also suppressed, and the symptoms of osteoarthritis were effectively alleviated. "This study is the first to conceptually demonstrate the feasibility of gene-induced stem cell 'young' factors in the treatment of osteoarthritis, providing a new solution for the intervention of aging-related diseases, with a broad perspective in geriatrics and regenerative medicine. Application prospects," said Liu Guanghui, the author of the paper.
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